This invention relates to novel dihydropyridine soft drugs and related pharmaceutical compositions useful in treating conditions such as hypersensitivity, allergy, asthma, bronchospasm, dysmenorrhea, esophageal spasm, glaucoma, premature labor, urinary tract disorders, gastrointestinal motility disorders and cardiovascular disorders.
Dihydropyridines
Dihydropyridines inhibit L-type voltage-sensitive Ca2+ channels and have effects on vascular smooth muscle such as dilating blood vessels and lowering blood pressure (U.S. Pat. No. 6,017,965 to Mueller et al.). U.S. Pat. No. 5,708,177 to Straub discloses a process for the preparation of optically active ortho-substituted 4-aryl- or heteroaryl-1,4-dihydropyridines by oxidation and subsequent reduction from their opposite enantiomers. U.S. Pat. No. 5,075,440 to Wustrow et al. discloses pyrido[2,3-f][1,4]thiazepiries and pyrido[3,2-b][1,5]benzothiazepines which are useful as calcium channel antagonists with cardiovascular, antiasthmatic and antibroncho constriction activity. U.S. Pat. Nos. 4,879,384 and 4,845,225, both to Schwender and Dodd, disclose substituted thiacycloalkeno [3,2-b]pyridines which are also useful as calcium channel antagonists with cardiovascular, antiasthmatic and antibronchoconstrictor activity. U.S. Pat. Nos. 4,285,955 and 4,483,985 to Wehinger et al. disclose acyclic sulfone substitution on simple dihydropyridines which possess calcium channel antagonist activity. U.S. Pat. No. 4,532,248 to Franckowiak et al. discloses a broad genus of dihydropyridines, including cyclic sulfones fused to a dihydropyridine nucleus. Cardiotonic activity is disclosed for the entire genus; however, these compounds are not calcium channel blockers. G. P. A. Pagani discloses 10-Phenyl-2H-thiopyranol[3,2-b]quinolines in J. Chem. Soc. Perkin Trans. 2, 1392 (1974). Many of these dihydropyridine drugs remain active after they enter the blood stream causing undesired systemic effects such as low blood pressure. Such side effects can limit the degree to which therapeutically effective doses of dihydropyridine drugs can be administered.
Soft Drugs
xe2x80x9cSoft drugsxe2x80x9d (also known as xe2x80x9cantedrugsxe2x80x9d) are biologically active drugs which are metabolically inactivated after they achieve their therapeutic role at their designed site of action. The use of soft drugs, instead of their non-inactivatable analogs, can avoid unwanted side effects.
No dihydropyridine soft drugs are known. However, soft drugs of non-dihydropyridine compounds are known generally (see, for example, Lee et al., 1998, Curr. Opin. Drug Disc. Dev. 1: 235-44). Plasma-labile soft drugs include, for example, carboxylic ester and thioester derivatives. Biggadike et al. report that incorporation of a xcex3-lactone or cyclic carbonate moiety onto the glucocorticoid nucleus provides compounds which are rapidly inactivated via plasma hydrolysis (J. Med. Chem. 43:19-21, 2000). U.S. Pat. Nos. 4,540,564 and 5,389,623 (both to Bodor) disclose drugs linked to dihydropyridine moieties which can enter the brain, where they are oxidized to a charged pyridinium species which is trapped in the brain.
Prokai-Tatra, J. M., Chem, Vol. 39, p. 4777 (1996) teaches that a leucine-enkephalin analogue can be modified with a chemical delivery system which is based on a retrometabolic drug design. The enkephaklin analogue is derivatized with a dihydropyricline moiety at the N-terminus and a lipophilic moiety at the C-terminus. After intravenous administration of the conjugate, an analgesic response is observed. It is postulated that the lipophilic modification at the C-terminus enables penetration into the central nervous system, while the dihydropyridine moiety undergoes oxidative transformation to generate a charged moiety which restricts the peptides from entering the circulatory system.
WO 99/12572 (Bodor et al.) provides peptide derivatives designed to deliver peptides having growth factor inhibitory activity (somatostatin analogs in particular) to the retina by sequential metabolism. The peptide derivatives, which comprise a dihydropyridine:pyridinium salt-type redox targetor moiety, a bulky lipophilic moiety and an amino acid/dipeptide/tripeptide spacer, have use in the prevention and treatment of diabetic retinopathy.
This invention provides novel dihydropyridine soft drugs of Formula I as defined hereinbelow, 
as well as methods for making same. This invention also provides a pharmaceutical composition comprising the instant compound and a pharmaceutically acceptable carrier.
This invention further provides a method of treating a subject suffering from a disorder whose alleviation is mediated by the reduction of calcium ion influx into cells whose actions contribute to the disorder, which method comprises administering to the subject a therapeutically effective dose of the instant pharmaceutical composition.
This invention still further provides a method of inhibiting in a subject the onset of a disorder whose alleviation is mediated by the reduction of calcium ion influx into cells whose actions contribute to the disorder, which method comprises administering to the subject a prophylactically effective dose of the instant pharmaceutical composition.
Finally, this invention provides an apparatus for administering to a subject the instant pharmaceutical composition, comprising a container and the pharmaceutical composition therein, whereby the container has a means for delivering to the subject a therapeutic and/or prophylactic dose of the pharmaceutical composition.
This invention provides novel dihydropyridine soft drug analogs. These soft drugs are characterized by a chemically labile moiety bound to an ester group in turn bound to the dihydropyridine ring structure. The instant soft drugs permit the dihydropyridine moieties thereof to exert their effect locally, and to subsequently be metabolized in the blood stream, thereby reducing unwanted systemic effects (e.g. low blood pressure). Use of such soft drugs permits the administration of greater doses of dihydropyridine compounds without subjecting the subject to intolerable systemic effects.
Specifically, this invention provides a compound of Formula I, 
or a pharmaceutically acceptable salt thereof, wherein
(a) "PHgr" is a dihydropyridine ring-containing moiety, which moiety, is bound to the carbonyl carbon of Formula (I) via a carbon atom in the meta position with respect to the pyridine ring nitrogen atom; and
(b) R1 is selected from -alkyl-OH, alkylamine, lactone, cyclic carbonate, alkyl-substituted cyclic carbonate, aryl-substituted cyclic carbonate, -aryl-C(O)ORxe2x80x2, -alkyl-aryl-C(O)ORxe2x80x2, -alkyl-OC(O)Rxe2x80x2, -alkyl-C(O)Rxe2x80x2, -alkyl-C(O)ORxe2x80x2, -alkyl-N(Rxe2x80x3)C(O)Rxe2x80x2, and -alkyl-N(Rxe2x80x3)C(O)ORxe2x80x2, wherein
Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, amino, alkyl, aryl, aryl-fused cycloalkyl and heterocyclyl, the amino, alkyl, aryl, aryl-fused cycloalkyl and heterocyclyl being optionally substituted with halogen, cyano, NO2, lactone, amino, alkylamino, aryl-substituted alkylamino, amide, carbamate, carbamoyl, cyclic carbonate, alkyl, halogen-substituted alkyl, arylalkyl, alkoxy, heterocyclyl and/or aryl (the aryl being optionally substituted with OH, halogen, cyano, NO2, alkyl, amino, dimethylamino, alkoxy, alkylsulfonyl, C1-4 carboalkcxy, alkylthio and/or trifluoromethyl).
In one embodiment of the instant invention, R1 is selected from -alkyl-OH, alkylamine, lactone, cyclic carbonate, alkyl- or aryl-substituted cyclic carbonate, -aryl-C(O)ORxe2x80x2, -alkyl-aryl-C(O)ORxe2x80x2, -alkyl-C(O)Rxe2x80x2, -alkyl-N(Rxe2x80x3)C(O)Rxe2x80x2, and -alkyl-N(Rxe2x80x3)C(O)ORxe2x80x2. In a preferred embodiment of the compounds of Formula I, R1 is -alkyl-aryl-C(O)ORxe2x80x2 or -alkyl-N(Rxe2x80x3)C(O)Rxe2x80x2. In another preferred embodiment of the compounds of Formula I, R1 is -alkyl-OC(O)Rxe2x80x2 or -alkyl-C(O)ORxe2x80x2. In yet another preferred embodiment of the compounds of Formula I, R1 is selected from xe2x80x94(CH2)2OC(O)CH(CH2CH3)2, xe2x80x94(CH2)2OC(O)CH(CH3)2, xe2x80x94(CH2)2OC(O)PHxe2x80x94OCH(CH3)2, xe2x80x94CH2OC(O)CH2N(CH3)CH2PH, xe2x80x94CH2OC(O)CH2xe2x80x94PHxe2x80x94N(CH3)2, and CH2OC(O)CH(CH2)6.
Compounds of Formulae Ia through Ih are exemplary of the compounds of Formula I. Specifically, this invention provides compounds of Formula Ia, 
wherein R1 is as described above, and
(a) R2, R3, R4, R5 and R6 are independently selected from hydrogen, OH, halogen, cyano, NO2, alkyl, C1-8 alkoxy, C1-8 alkylsulfonyl, C1-4 carboalkoxy, C1-8 alkylthio, difluoromethoxy, difluoromethylthio, trifluoromethyl and oxadiazole (formed by R2 and R3);
(b) R7 is connected to the bis-sulfone ring via a single or double bond, as applicable, and is selected from hydrogen, alkylhydroxy, alkenyl, amino, phenyl, benzyl, C1-8 straight or branched alkyl, trifluoromethyl, alkoxymethyl, C3-7 cycloalkyl, substituted benzyl, formyl, acetyl, t-butyloxy carbonyl, propionyl, substituted alkyl and Rxe2x80x2xe2x80x3CH2Cxe2x95x90O, wherein
(i) the substituted benzyl is substituted with halogen, trifluoromethyl, C1-8 straight and/or branched alkyl or C1-8 alkoxy, (ii) the substituted alkyl is substituted with amino, dialkyl amino, C1-8 alkoxy, hydroxy and/or halogen, and (iii) Rxe2x80x2xe2x80x3 is amino, dialkyl amino, C1-8 alkoxy, hydroxy or halogen;
(c) R8 is selected from hydrogen, amino, alkyl, aryl, trifluoromethyl, alkoxymethyl, 2-thieno and 3-thieno; and
(d) m, n, and their sum are each an integer from 0 to 4.
This invention also provides compounds of Formula Ib, 
wherein R1 is as described above, and
(a) R2, R3, R4, R5 and R6 are independently selected from hydrogen, OH, halogen, cyano, NO2, alkyl, C1-8 alkoxy, C1-8 alkylsulfonyl, C1-4 carboalkoxy, C1-8 alkylthio, difluoromethoxy, difluoromethylthio, trifluoromethyl and oxadiazole (formed by R2 and R3);
(b) R7 is SO or SO2; and
(c) R8 is selected from hydrogen, amino, alkyl, aryl, trifluoromethyl, alkoxymethyl, 2-thieno and 3-thieno.
In one embodiment of Formula Ib, R2, R3, R4, R5 and R6 are independently selected from hydrogen, halogen, trifluoromethyl and NO2, and R8 is methyl.
This invention also provides compounds of Formula Ic, 
wherein R1 is as described above, and
(a) R2, R3, R4, R5 and R6 are independently selected from hydrogen, OH, halogen, cyano, NO2, alkyl, C1-8 alkoxy, C1-8 alkylsulfonyl, C1-4 carboalkoxy, C1-8 alkylthio, difluoromethoxy, difluoromethylthio, trifluoromethyl and oxadiazole (formed by R2 and R3); and
(b) R8 is selected from hydrogen, amino, alkyl, aryl, trifluoromethyl, alkoxymethyl, 2-thieno and 3-thieno.
In one embodiment of Formula Ic, R8 is methyl and R2, R3, R4, R5 and R6 are independently selected from hydrogen, halogen, trifluoromethyl, and NO2.
This invention also provides compounds of Formula Id, 
wherein R1 is as described above, and
(a) R2, R3, R4, R5 and R6 are independently selected from hydrogen, OH, halogen, cyano, NO2, alkyl, C1-8 alkoxy, C1-8 alkylsulfonyl, C1-4 carboalkoxy, C1-8 alkylthio, difluoromethoxy, difluoromethylthio, trifluoromethyl and oxadiazole (formed by R2 and R3);
(b) R8 is selected from hydrogen, amino, alkyl, aryl, trifluoromethyl, alkoxymethyl, 2-thieno and 3-thieno; and
(c) R9 is oxygen or sulfur.
In one embodiment of Formula Id, R9 is oxygen. In a further embodiment, R8 is methyl, and R2, R3, R4, R5 and R6 are independently selected from hydrogen, halogen, trifluoromethyl and NO2.
This invention also provides compounds of Formula Ie, 
wherein R1 is as described above, and
(a) R2, R3, R4, R5 and R6 are independently selected from hydrogen, OH, halogen, cyano, NO2, alkyl, C1-8 alkoxy, C1-8 alkylsulfonyl, C1-4 carboalkoxy, C1-8 alkylthio, difluoromethoxy, difluoromethylthio, trifluoromethyl and oxadiazole (formed by R2 and R3); and
(b) R8 is selected from hydrogen, amino, alkyl, aryl, trifluoromethyl, alkoxymethyl, 2-thieno and 3-thieno.
In one embodiment of Formula Ie, R8 is methyl and R2, R3, R4, R5 and R6 are independently selected from hydrogen, halogen, trifluoromethyl and NO2.
This invention also provides compounds of Formula If, 
wherein R1 is as described above, and
(a) R2, R3, R4, R5 and R6 are independently selected from hydrogen, OH, halogen, cyano, NO2, alkyl, C1-8 alkoxy, C1-8 alkylsulfonyl, C1-4 carboalkoxy, C1-8 alkylthio, difluoromethoxy, difluoromethylthio, trifluoromethyl and oxadiazole (formed by R2 and R3);
(b) R10 is selected from aryl, 3-pyridyl, 2-thieno and 3-thieno; and
(c) p is an integer from 1 to 5.
In one embodiment of Formula If, p is 2. In another embodiment, R10 is selected from phenyl, 3-pyridyl, and 2-thieno. In a further embodiment, R2, R3, R4, R5 and R6 are independently selected from hydrogen, OH, halogen, trifluoromethyl, and NO2.
This invention also provides compounds of Formula Ig, 
wherein R1 is as described above, and
(a) Z is N or CR2;
(b) Y is N or CR3;
(c) R2, R3, R4, R5 and R6 are independently selected from hydrogen, OH, halogen, cyano, NO2, alkyl, C1-8 alkoxy, C1-8 alkylsulfonyl, C1-4 carboalkoxy, C1-8 alkylthio, difluoromethoxy, difluoromethylthio, trifluoromethyl and oxadiazole (formed by R2 and R3);
(d) R8 is selected from hydrogen, amino, alkyl, aryl, trifluoromethyl, alkoxymethyl, 2-thieno and 3-thieno;
(e) R11 is selected from hydrogen, amino, alkyl, aryl, trifluoromethyl, alkoxymethyl, 2-thieno and 3-thieno; and
(f) R12 is selected from hydrogen, -alkyl-OH, alkylamine, lactone, cyclic carbonate, alkyl-substituted cyclic carbonate, aryl-substituted cyclic carbonate, -aryl-C(O)ORxe2x80x2, -alkyl-OC(O)Rxe2x80x2, -alkyl-C(O)Rxe2x80x2, -alkyl-C(O)ORxe2x80x2, -alkyl-N(Rxe2x80x3)C(O)Rxe2x80x2, -alkyl-N(Rxe2x80x3)C(O)ORxe2x80x2, -alkyl-S-Rxe2x80x2, alkyl, aryl-substituted alkyl, aryl, xe2x80x94(CH2)2N(CH3)CH2PH, xe2x80x94CH2CH2xe2x80x94N(Me)xe2x80x94CH2xe2x80x94 heteroaryl, 3-piperidyl, N-substituted 3-piperidyl, and N-substituted 2-pyrrolidinyl methylene, wherein
(i) Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, amino, alkyl, aryl, aryl-fused cycloalkyl and heterocyclyl, the amino, alkyl, aryl, aryl-fused cycloalkyl and heterocyclyl being optionally substituted with halogen, cyano, NO2, lactone, amino, alkylamino, aryl-substituted alkylamino, amide, carbamate, carbamoyl, cyclic carbonate, alkyl, halogen-substituted alkyl, arylalkyl, alkoxy, heterocyclyl and/or aryl (the aryl being optionally substituted with OH, halogen, cyano, NO2, alkyl, amino, dimethylamino, alkoxy, alkylsulfonyl, C1-4 carboalkoxy, alkylthio and/or trifluoro methyl);
(ii) the alkyl may be substituted with alkoxy, C2-C8 alkanoyloxy, phenylacetyloxy, benzoyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, carboalkoxy, and/or NRIVRV, wherein
RIV and RV are independently selected from hydrogen, alkyl, phenyl, benzyl and phenethyl, or RIV and RV together form a heterocyclic ring selected from the group consisting of piperidino, pyrrolidino, morpholino, thiomorpholino, piperazino, 2-thieno, 3-thieno and an N-substituted derivative of the heterocyclic rings (the N-substituted derivative being substituted with hydrogen, alkyl, benzyl, benzhydryl and/or phenyl optionally substituted with hydrogen, NO2, halogen, alkyl, alkoxy and/or trifluoromethyl); and
(iii) the N-substituted 3-piperidyl and the N-substituted 2-pyrrolidinyl methylene are optionally substituted with alkyl or benzyl.
In one embodiment of Formula Ig, R12 is selected from hydrogen, alkyl, and aryl-substituted alkyl. In another embodiment, R12 is selected from hydrogen, xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH(CH3)2, xe2x80x94CH(CH3)CH2CH3, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94CH3, xe2x80x94CH2CH2xe2x80x94Sxe2x80x94CH3, cyclopentane, and benzyl. In two further embodiments, Z is CR2 and Y is CR3.
This invention also provides compounds of Formula Ih, 
wherein R1 is as described above, and
(a) Z is N or CR2;
(b) Y is N or CR3;
(c) R2, R3, R4, R5 and R6 are independently selected from hydrogen, OH, halogen, cyano, NO2, alkyl, C1-8 alkoxy, C1-8 alkylsulfonyl, C1-4 carboalkoxy, C1-8 alkylthio, difluoromethoxy, difluoromethylthio, trifluoromethyl and oxadiazole (formed by R2 and R3);
(d) R8 is selected from hydrogen, amino, alkyl, aryl, trifluoromethyl, alkoxymethyl, 2-thieno and 3-thieno;
(e) R11 is selected from hydrogen, amino, alkyl, aryl, trifluoromethyl, alkoxymethyl, 2-thieno and 3-thieno; and
(f) R12 is selected from hydrogen, -alkyl-OH, alkylamine, lactone, cyclic carbonate, alkyl-substituted cyclic carbonate, aryl-substituted cyclic carbonate, -aryl-C(O)ORxe2x80x2, -alkyl-OC(O)Rxe2x80x2, -alkyl-C(O)Rxe2x80x2, -alkyl-C(O)ORxe2x80x2, -alkyl-N(Rxe2x80x3)C(O)Rxe2x80x2, -alkyl-N(Rxe2x80x3)C(O)ORxe2x80x2, -alkyl-S-Rxe2x80x2, alkyl, aryl-substituted alkyl, aryl, xe2x80x94(CH2)2N(CH3)CH2PH, xe2x80x94CH2CH2xe2x80x94N(Me)xe2x80x94CH2xe2x80x94 heteroaryl, 3-piperidyl, N-substituted 3-piperidyl, and N-substituted 2-pyrrolidinyl methylene, wherein
(i) Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, amino, alkyl, aryl, aryl-fused cycloalkyl and heterocyclyl, the amino, alkyl, aryl, aryl-fused cycloalkyl and heterocyclyl being optionally substituted with halogen, cyano, NO2, lactone, amino, alkylamino, aryl-substituted alkylamino, amide, carbamate, carbamoyl, cyclic carbonate, alkyl, halogen-substituted alkyl, arylalkyl, alkoxy, heterocyclyl and/or aryl (the aryl being optionally substituted with OH, halogen, cyano, NO2, alkyl, amino, dimethylamino, alkoxy, alkylsulfonyl, C1-4 carboalkoxy, alkylthio and/or trifluoromethyl);
(ii) the alkyl may be substituted with alkoxy, C2-C8 alkanoyloxy, phenylacetyloxy, benzoyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, carboalkoxy, and/or NRIVRV, wherein
RIV and RV are independently selected from hydrogen, alkyl, phenyl, benzyl and phenethyl, or RIV and RV together form a heterocyclic ring selected from the group consisting of piperidino, pyrrolidino, morpholino, thiomorpholino, piperazino, 2-thieno, 3-thieno and an N-substituted derivative of the heterocyclic rings (the N-substituted derivative being substituted with hydrogen, alkyl, benzyl, benzhydryl and/or phenyl optionally substituted with hydrogen, NO2, halogen, alkyl, alkoxy and/or trifluoromethyl); and
(iii) the N-substituted 3-piperidyl and the N-substituted 2-pyrrolidinyl methylene are optionally substituted with alkyl or benzyl.
In one embodiment of Formula Ih, R12 is aryl, and preferably phenyl. In another embodiment, Z is CR2.
The following compounds are preferred embodiments of the present invention:
5H-[1,4]dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-(2-ethyl-1-oxobutoxy)ethyl ester, 1,1,4,4-tetraoxide;
5H-[1,4]dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2,3-dichlorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-(2-methyl-1-oxopropoxy)ethyl ester, 1,1,4,4-tetraoxide;
5H-[1,4]dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-[[4-(1-methylethoxy)lbenzoyl] oxy]ethyl ester, 1,1,4,4-tetraoxide;
5H-[1,4]dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-[(4-methyl-1-oxopentyl)oxy]ethyl ester, 1,1,4,4-tetraoxide;
5H-[1,4]dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-(2-methyl-1-oxo-3-phenylpropoxy) ethyl ester, 1,1,4,4-tetraoxide;
5H-[1,4]dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-(3-methyl-1-oxobutoxy)ethyl ester, 1,1,4,4-tetraoxide;
5H-[1,4]dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-[(cycloheptylcarbonyl)oxy]ethyl ester, 1,1,4,4-tetraoxide;
5H-[1,4]dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-[(3-methoxybenzoyl)oxy]ethyl ester, 1,1,4,4-tetraoxide;
5H-[1,4]dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 3-(benzoyloxy)propyl ester, 1,1,4,4-tetraoxide;
5H-[1,4]dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-[[(1,2,3,4-tetrahydro-2-naphthalenyl)carbonyl]oxy]ethyl ester, 1,1,4,4-tetraoxide;
5H-[1,4]dithiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-[[4-(trifluoromethyl)benzoyl]oxy]ethyl ester, 1,1,4,4-tetraoxide;
2H,6H-[1,5]dithiocino[3,2-b]pyridine-9-carboxylic acid, 10-(2-chloro-6-fluorophenyl)-3,4,7,10-tetrahydro-8-methyl-, 2-[[4-(1-methylethoxy)benzoyl]oxy] ethyl ester, 1,1,5,5-tetraoxide;
2H,6H-[1,5]dithiocino[3,2-b]pyridine-9-carboxylic acid, 10-(2-chloro-6-fluorophenyl)-3,4,7,10-tetrahydro-8-methyl-, 2-[(3-cyanobenzoyl)oxy]ethyl ester, 1,1,5,5-tetraoxide;
2H,6H-[1,5]dithiocino[3,2-b]pyridine-9-carboxylic acid, 10-(2-chloro-6-fluorophenyl)-3,4,7,10-tetrahydro-8-methyl-, 2-[(cyclohexylcarbonyl)oxy]ethyl ester, 1,1,5,5-tetraoxide;
1H-[1,5]benzodithiepino[3,2-b]pyridine-3-carboxylic acid, 4-(2-chloro-6-fluorophenyl)-4,11-dihydro-2-methyl-, 2-(acetyloxy)ethyl ester, 5,5,10,10-tetraoxide;
1H-[1,5]benzodithiepino[3,2-b]pyridine-3-carboxylic acid, 4-(2-chloro-6-fluorophenyl)-4,11-dihydro-2-methyl-, 2-(benzoyloxy)ethyl ester, 5,5,10,10-tetraoxide;
1H-[1,5]benzodithiepino[3,2-b]pyridine-3-carboxylic acid, 4-(2-chloro-6-fluorophenyl)-4,11-dihydro-2-methyl-, 2-[(cyclohexylcarbonyl)oxy]ethyl ester, 5,5,10,10-tetraoxide;
1H-[1,5]benzodithiepino[3,2-b]pyridine-3-carboxylic acid, 4-(2-chloro-6-fluorophenyl)-4,11-dihydro-2-methyl-, 2-[[(1,1-dimethylethoxy)carbonyl]amino] ethyl ester, 5,5,10,10-tetraoxide;
1H-[1,5]benzodithiepino[3,2-b]pyridine-3-carboxylic acid, 4-(2-chloro-6-fluorophenyl)-4,11-dihydro-2-methyl-, 2-aminoethyl ester, 5,5,10,10-tetraoxide;
1H-[1,5]benzodithiepino[3,2-b]pyridine-3-carboxylic acid, 4-(2-chloro-6-fluorophenyl)-4,11-dihydro-2-methyl-, tetrahydro-2-oxo-3-furanyl ester, 5,5,10,10-tetraoxide;
1H-[1,5]benzodithiepino[3,2-b]pyridine-3-carboxylic acid, 4-(2-chloro-6-fluorophenyl)-4,11-dihydro-2-methyl-, 2-(2,2-dimethyl-1-oxopropoxy)ethyl ester, 5,5,10,10-tetraoxide;
1H-[1,5]benzodithiepino[3,2-b]pyridine-3-carboxylic acid, 4-(2-chloro-6-fluorophenyl)-4,11-dihydro-2-methyl-, 2-(benzoylamino)ethyl ester, 5,5,10,10-tetraoxide;
1H-[1,5]benzodithiepino[3,2-b]pyridine-3-carboxylic acid, 4-(2-chloro-6-fluorophenyl)-4,11-dihydro-2-methyl-, 2-[[(2S)-2-(6-methoxy-2-naphthalenyl)-1-oxopropyl]oxy]ethyl ester, 5,5,10,10-tetraoxide;
1H-[1,5]benzodithiepino[3,2-b]pyridine-3-carboxylic acid, 4-(2-chloro-6-fluorophenyl)-4,11-dihydro-2-methyl-, 2-[[(2E)-1-oxo-3-phenyl-2-propenyl]oxy] ethyl ester, 5,5,10,10-tetraoxide;
5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2,3-dichlorophenyl)-2,3,6,9-tetrahydro-7-methyl-, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, 1,1-dioxide;
5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2,3-dichlorophenyl)-2,3,6,9-tetrahydro-7-methyl-, (2-oxo-5-phenyl-1,3-dioxol-4-yl)methyl ester, 1,1-dioxide;
5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chlorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-hydroxyethyl ester, 1,1-dioxide;
5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chlorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-(2-methyl-1-oxopropoxy)ethyl ester, 1,1-dioxide;
5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-(2-methyl-1-oxopropoxy)ethyl ester, 1,1-dioxide;
5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-[(cyclopropylcarbonyl)oxy]ethyl ester, 1,1-dioxide;
5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-(acetyloxy)ethyl ester, 1,1-dioxide;
5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-[(cyclohexylcarbonyl)oxy]ethyl ester, 1,1-dioxide;
5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chloro-6-fluorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 2-(benzoyloxy)ethyl ester, 1,1-dioxide;
5H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylic acid, 9-(2-chlorophenyl)-2,3,6,9-tetrahydro-7-methyl-, 3-(benzoyloxy)propyl ester, 1,1-dioxide;
3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-, 3-methyl 5-(tetrahydro-2-oxo-3-furanyl) ester;
3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-, 3-methyl 5-[2-(tetrahydro-2-oxo-3-furanyl)ethyl] ester;
3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-, 3-methyl 5-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl] ester; and
3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-, 3-methyl 5-[(2-oxo-5-phenyl-1,3-dioxol-4-yl)methyl] ester.
Unless specified otherwise, the term xe2x80x9calkylxe2x80x9d refers to a straight, branched or cyclic substituent consisting solely of carbon and H with no unsaturation. The term xe2x80x9calkoxyxe2x80x9d refers to O-alkyl where alkyl is as defined. Aryl substituents include, for example, phenyl, naphthyl, diphenyl, fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl, carboethoxyphenyl, acetyl phenyl, ethoxyphenyl, phenoxyphenyl, hyd roxyphenyl, carboxyphenyl, trifluoromethylphenyl, methoxyethylphenyl, acetamidophenyl, tolyll, xylyl, dimethylcarbamylphenyl, xe2x80x94(CH2)2N(CH3)CH2PH, xe2x80x94CH2CH2xe2x80x94N(Me)xe2x80x94CH2xe2x80x94 heteroaryl and the like. The term xe2x80x9chaloxe2x80x9d means fluoro, chloro, bromo and iodo. The symbol xe2x80x9cPhxe2x80x9d or xe2x80x9cPHxe2x80x9d refers to phenyl. xe2x80x9cIndependentlyxe2x80x9d means that when there are more than one substituent, the substitutents may be different.
The compounds of the instant invention are asymmetric in the dihydropyridine ring at the 4-position and thus exist as optical antipodes. As such, all possible optical isomers, antipodes, enantiomers, and diastereomers resulting from additional asymmetric centers that may exist in optical antipodes, racemates and racemic mixtures thereof are also part of this invention. The antipodes can be separated by methods known to those skilled in the art such as, for example, fractional recrystallization of diastereomeric salts of enantiomerically pure acids. Alternatively, the antipodes can be separated by chromatography in a Pirkle type column.
As used herein, the phrase xe2x80x9cpharmaceutically acceptable saltxe2x80x9d means a salt of the free base which possesses the desired pharmacological activity of the free base and which is neither biologically nor otherwise undesirable. These salts may be derived from inorganic or organic acids. Examples of inorganic acids are hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. Examples of organic acids are acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, methyl sulfonic acid, salicyclic acid and the like.
The instant compounds can be prepared using readily available starting materials and reaction steps well known in the art (Edema et al. J. Org. Chem. 58: 5624-7, 1993; Howard et al., J. Amer. Chem. Soc. 82:158-64, 1960).
This invention also provides a pharmaceutical composition comprising any of the instant compounds and a pharmaceutically acceptable carrier.
Pharmaceutical compositions containing a compound of the present invention as the active ingredient in intimate admixture with a pharmaceutical carrier can be prepared according to conventional pharmaceutical techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, such as systemic administration including but not limited to intravenous, oral, nasal or parenteral. In preparing the compositions in oral dosage form, any of the usual pharmaceutical carriers may be employed, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, syrup and the like in the case of oral liquid preparations (for example, suspensions, elixirs and solutions), and carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations (for example, powders, capsules and tablets).
In one embodiment, the compounds of the instant invention are administered by inhalation. For inhalation administration, the compounds can be in a solution intended for administration by metered dose inhalers, or in a form intended for a dry powder inhaler or insufflator. More particularly, the instant compounds can be conveniently delivered in the form of an aerosol spray from a pressurized container, a pack or a nebuliser with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromiethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. The dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges made of a pharmaceutically acceptable material such as gelatin for use in an inhaler or insufflator can be formulated to contain a powder mix of the compound and a suitable powder base such as lactose or starch.
Because of their ease of administration, tablets and capsules represent an advantageous oral dosage unit form wherein solid pharmaceutical carriers are employed. If desired, tablets can be sugar-coated or enteric-coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, though other ingredients to aid solubility or to act as preservatives can be included. Injectable suspensions can also be prepared, wherein appropriate liquid carriers, suspending agents and the like are employed. The instant compounds can also be administered in the form of an aerosol, as discussed above.
The compounds of the present invention inhibit the uptake of calcium ions into smooth muscle cells, and therefore act to relax or prevent calcium ion-mediated contraction of smooth muscle tissue.
Thus, this invention further provides a method of treating a subject suffering from a disorder whose alleviation is mediated by the reduction of calcium ion influx into cells whose actions contribute to the disorder, which method comprises administering to the subject a therapeutically effective dose of the instant pharmaceutical composition. By way of example, in a subject suffering from asthma, the subject""s airways are constricted due to inflammation of airway smooth muscle cells (xe2x80x9cSMC""sxe2x80x9d). Reducing the calcium influx into the SMC""s, whose action (i.e., inflammation) contributes to the disorder, would be expected to alleviate the disorder.
This invention still further provides a method of inhibiting in a subject the onset of a disorder whose alleviation is mediated by the reduction of calcium ion influx into cells whose actions contribute to the disorder, which method comprises administering to the subject a prophylactically effective dose of the instant pharmaceutical composition.
In one embodiment, the disorder is selected from the group consisting of hypersensitivity, allergy, asthma, bronchospasm, dysmenorrhea, esophageal spasm, glaucoma, premature labor, a urinary tract disorder, a gastrointestinal motility disorder and a cardiovascular disorder. In the preferred embodiment, the disorder is asthma. The cardiovascular disorder can be, for example, hypertension, ischemia, angina, congestive heart failure, myocardial infarction or stroke.
As used herein, xe2x80x9ctreatingxe2x80x9d a disorder means eliminating or otherwise ameliorating the cause and/or effects thereof. xe2x80x9cInhibitingxe2x80x9d the onset of a disorder means preventing, delaying or reducing the likelihood of such onset.
The term xe2x80x9csubjectxe2x80x9d includes, without limitation, any animal or artificially modified animal. In the preferred embodiment, the subject is a human.
Methods are known in the art for determining therapeutically and prophylactically effective doses for the instant pharmaceutical composition. The effective dose for administering the pharmaceutical composition to a human, for example, can be determined mathematically from the results of animal studies. In one embodiment, the instant pharmaceutical composition contains a per dosage unit (e.g., tablet, capsule, powder, injection, teaspoonful and the like) from about 0.001 to about 100 mg/kg, and preferably from about 0.01 to about 20 mg/kg of the instant compound.
This invention further provides an apparatus for administering to a subject the instant pharmaceutical composition, comprising a container and the pharmaceutical composition therein, whereby the container has a means for delivering to the subject a therapeutic and/or prophylactic dose of the pharmaceutical composition. In the preferred embodiment, the apparatus is an aerosol spray device for treating and/or preventing asthma via topical respiratory administration.
Finally, this invention provides processes for preparing the compound of Formula I. 
One process for preparing the compound of Formula I comprises reacting the compound of Formula 1a with R1Br or R1Cl in the presence of 
K2CO3 or CsCO3 in dimethylformamide to form the compound of Formula I.
Another process for preparing the compound of Formula I comprises converting the compound of Formula 2a 
to the compound of Formula I in the presence of formic acid.
Yet another process for preparing the compound of Formula I comprises converting the compound of Formula 2b 
to the compound of Formula I in the presence of NaOH (aq).
This invention will be better understood by reference to the Experimental Details that follow, but those skilled in the art will readily appreciate that these are only illustrative of the invention as described more fully in the claims which follow thereafter. Additionally, throughout this application, various publications are cited. The disclosure of these publications is hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains.
Experimental Details
A. Schemes and Syntheses
Procedures for making dihydropyridines are well documented in the art, as exemplified by Eistert et al. (Chem. Ber. 110, 1069-1085,1977), G. A. Pagani (J. Chem. Soc., Perkin Trans. 2, 1392-7, 1974), Mason et al. (J. Chem. Soc. (C) 2171-76, 1967), E. A. Fehnel (J. Amer. Chem. Soc. 74,1569-74, 1952), and M. Seiyaku (Japan Patent Application No. 58201764, 1984).
The compounds of Formula I can be made in accordance with Scheme 1, wherein "PHgr" and R1 are as described above, preferably in the presence of K2CO3 or CsCO3 in an organic solvent such as dimethylformamide (DMF): 
The compounds of Formula I may also be made in accordance with Scheme 2, wherein "PHgr" and R1 are as described above, preferably in the presence of formic acid or NaOH (aq), respectively: 
The examples below describe in greater detail the chemical syntheses of representative compounds of the present invention. The rest of the compounds disclosed herein can be prepared similarly in accordance with one or more of these methods. No attempt has been made to optimize the yields obtained in these syntheses, and it would be clear to one skilled in the art that variations in reaction times, temperatures, solvents, and/or reagents could be used to increase such yields.